Angiogenesis (Angiogenesis), i.e., new blood vessel constructed from existing blood vessel, is an important mechanism of many physiological and pathological processes occurrence. Under normal circumstances, angiogenesis occurs only in embryonic development, wound healing and menstrual cycles of women. Abnormal angiogenesis may occur under pathological conditions (Shibuya M. BMB. Rep. 2008; 41(4): 278-86), especially during the growth of tumors which requires new blood vessels to supply nutrients and excrete metabolites. Endothelial proliferation and new blood vessel formation promote an increase in solid tumors.
The key signal system regulates endothelial cell proliferation and migration is vascular endothelial growth factor (VEGF) and its receptor (VEGFR-1, -2 and -3). VEGFR-2 has a higher affinity and kinase activity, and plays a more important role in directly regulating angiogenesis, mitogenic signaling and permeability increasement. Vascular endothelial growth factor receptors (VEGFRs) are expressed at high levels in many human solid tumors, including glioma, lung cancer, breast cancer, renal cancer, ovarian cancer and gastrointestinal cancer.
VEGF/VEGFR-2 signaling pathway plays a critical role in tumor angiogenesis, and can inhibit angiogenesis by blocking or interfering with VEGF/VEGFR-2 signaling pathway in order to achieve the effect of controlling the growth of tumors. Thus, many small molecule VEGFR-2 inhibitors are being developed, some of which are useful in treating angiogenesis disorder related disease such as inflammatory diseases, retinopathy and so on. The present inventors have designed and synthesized naphthalene amides having novel structures and found small molecule VEGFR-2 inhibitors having good activity in the enzyme level and cellular level by optimizing the substituents.